Haemostatic biomarkers are associated with long-term recurrent vascular events after ischaemic stroke

Abstract

Ischaemic stroke patients continue to be at risk for recurrent vascular events for many years. Predictors of long-term prognosis are needed. It was the objective of this study to investigate levels of four haemostatic proteins as long-term predictors of recurrent vascular events after ischaemic stroke. We prospectively followed 548 ischaemic stroke patients, 18-69 years, and registered recurrent vascular events. Plasma levels of tissue-type plasminogen activator (t-PA), von Willebrand factor (VWF), fibrinogen and thrombin activatable fibrinolysis inhibitor activation peptide (TAFI-AP) were measured three months after index stroke. Cox regression models were used to assess associations to outcomes for single biomarkers and for a combined biomarker measure. For single biomarkers significantly associated with any of the outcomes, we performed subanalyses stratified for age, sex, diabetes and atherosclerosis. During 5,637 person-years of follow-up, we registered 74 vascular deaths, 90 recurrent strokes and 62 coronary events. Levels of t-PA, VWF and fibrinogen were significantly associated with vascular death and coronary events. After adjustment, the association between t-PA and vascular death remained (HR per 1 SD increase in plasma level 1.27, 95 % CI 1.00-1.61, p=0.047). The combined effect of t-PA, VWF and fibrinogen was associated with coronary events (adjusted HR 1.35, 1.02-1.80, p=0.04). In non-diabetic patients, an association with coronary events was seen for VWF levels (adjusted HR 2.23, 1.45-3.43, p<0.01). In conclusion, plasma levels of haemostatic factors were associated with vascular death and coronary events, but not with recurrent stroke. Our results suggest that the predictive value of biomarkers differ by specific outcome measure and subgroup of patients.

FIND Stroke Recovery Study (FIND): rationale and protocol for a longitudinal observational cohort study of trajectories of recovery and biomarkers poststroke

“…Clinically established blood biomarkers are commonly based on measurements of protein concentrations in plasma or serum. We and others have, for example, previously found plasma proteins with subtype-specific patterns, 54 55 protein concentrations associated with recurrent vascular events 56 57 as well as neurological and functional outcomes. 57–60 Here, planned analyses include multiomics profiling, on the metabolite, protein, RNA and DNA level, utilising the Swedish National infrastructure for state-of-the-art omics at Science for Life Laboratory (SciLifeLab), Uppsala and Stockholm, and the Bioinformatics and Data Centre, Gothenburg.…”

ADMA as a possible marker of endothelial damage. A study in young asymptomatic patients with cerebral small vessel disease

“…2. In a study analysing haemostatic markers of stroke recurrence (tPA, VWF and TAFI) their predictive value is consistent in coronary events but not in stroke 12 . 3.…”

Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

“…In the first SAHLSIS follow-up by Jood et al in 2012, levels of CPU activation peptide measured in 517 ischemic stroke survivors three months after the index event, but not simultaneously measured proCPU antigen levels, predicted future death and reoccurrence of vascular events (recurrent stroke, transient ischemic attack or coronary event; N = 37) in the first two years [31]. However, at 10-year follow-up, this association could not be confirmed [101]. De Bruijne et al described an association between proCPU antigen levels and an increased risk of premature peripheral arterial disease [59].…”

“…A first pair developed by this group allows the measurement of the amount of activation peptide that has been released through activation of proCPU (MA-T12D11/MA-T18A8-HRP). A second antibody pair measures the total amount of CPU + CPUi formed (MA-T30E5/MA-T17D7-HRP) [58,59,61,62,101]. Another assay that allows combined measurement of CPU and CPUi was published by Hulme et al [102].…”

“…Despite, the inconclusive results of CPU inhibition in various animal models, the first-in-man trials and phase II trial of DS-1040 and AZD9684 respectively showed increased D-dimer, a marker of fibrinolytic activity, in several patients which points towards stimulation of endogenous fibrinolysis [105,122,151]. As for the approach of using CPU inhibition as an adjuvant to tPA-mediated thrombolysis, reviews by Willemse et al and Foley et al on this topic suggest that CPU deficiency/inhibition may improve the thrombolytic efficacy of tPA [101,110,147]. Moreover, in co-administration with rtPA PTCI reduced thrombus weight in rat models of venous or arterial thrombosis where PTCI alone was ineffective [194].…”